Inhibition of α-ketoglutarate- and pyruvate dehydrogenase complexes in E-coli by a glutathione S-transferase containing a pathological length poly-Q domain:: A possible role of energy deficit in neurological diseases associated with poly-Q expansions?

At least seven adult-onset neurodegenerative diseases, including Huntington's disease (HD), are caused by genes containing expanded CAG triplets within their coding regions. The expanded CAG repeats give rise to extended stretches of polyglutamines (Q(n)) in the proteins expressed by the affected genes. Generally, n greater than or equal to 40 in affected individuals and less than or equal to 36 in clinically unaffected individuals. The expansion has been proposed to confer a "toxic gain of function" to the mutated protein. Poly-Q domains have recently been shown to be excellent substrates of tissue transglutaminase. We investigated the effects of expression of glutathione S-transferase constructs containing poly-Q inserts of various lengths (GSTQ(n) where n = 0, 10, 62 or 81) on the activity of some key metabolic enzymes in the host Escherischia coli - an organism not known to have transglutaminase activity. E. coli carrying the GSTQ(62) construct exhibited statistically significant decreases in the specific activities of oc-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC). Previous work has shown that KGDHC and PDHC activities are reduced in the brains of Alzheimer's disease (AD) patients. Our results suggest that KGDHC and PDHC may be particularly susceptible to the effects of a number of disparate insults, including those associated with AD and HD.